DOI: 10.1126/science.1089681. Diverse Psychotomimetics Act Through a Common Signaling Pathway

Diverse Psychotomimetics Act Through a Common Signaling Pathway

10.1126/science.1089681

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3′,5′-monophosphate (cAMP)–regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase–1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase–3 (GSK-3), cAMP response element–binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters—sensorimotor gating and repetitive movements—were strongly attenuated.

Bibliography

Svenningsson, P., Tzavara, E. T., Carruthers, R., Rachleff, I., Wattler, S., Nehls, M., McKinzie, D. L., Fienberg, A. A., Nomikos, G. G., & Greengard, P. (2003). Diverse Psychotomimetics Act Through a Common Signaling Pathway. Science, 302(5649), 1412â1415.

Authors 10

Per Svenningsson (first)
Eleni T. Tzavara (additional)
Robert Carruthers (additional)
Ilan Rachleff (additional)
Sigrid Wattler (additional)
Michael Nehls (additional)
David L. McKinzie (additional)
Allen A. Fienberg (additional)
George G. Nomikos (additional)
Paul Greengard (additional)

References 21 Referenced 267

10.1126/science.1070532
10.1146/annurev.pharmtox.41.1.237
10.1055/s-2007-979353
10.1001/archpsyc.1988.01800310020002
10.1038/378176a0
A. Abi-Darghamet al., Am. J. Psychiatry155, 761 (1998). (10.1176/ajp.155.6.761) / Am. J. Psychiatry (1998)
10.1126/science.124.3212.121
10.1001/archneurpsyc.1959.02340150095011
10.1176/ajp.130.1.61
10.1126/science.294.5544.1024
10.1007/s002130100811
10.1016/0301-0082(94)90039-6
10.1038/npp.1994.22
10.1038/310503a0
10.1016/S0021-9258(20)88248-9
10.1073/pnas.92.7.2682
10.1038/45251
P. Svenningsson R. Carruthers I. Rachleff P. Greengard unpublished observations.
10.1038/sj.mp.4001017
10.1016/S0896-6273(00)80245-7
Supported by the Stern Foundation and by NIH grants MH40899 and DA10044 (P.G.). P.S. is supported by a postdoctoral fellowship from Stiftelsen för Internationalisering av högre utbildning och forskning. We thank P. Ingrassia for help with animal breeding; G. L. Snyder J. A. Bibb A. C. Nairn and H. C. Hemmings Jr. for phospho-Thr 34 –DARPP-32 phospho-Thr 75 DARPP-32 phospho-Ser 130 DARPP-32 and DARPP-32 antibodies; and K. Knitkowski and J. Camara for technical assistance.

Dates

Type	When
Created	21 years, 9 months ago (Nov. 21, 2003, 12:14 a.m.)
Deposited	8 months, 2 weeks ago (Dec. 14, 2024, 7:36 a.m.)
Indexed	4 weeks ago (Aug. 2, 2025, 12:09 a.m.)
Issued	21 years, 9 months ago (Nov. 21, 2003)
Published	21 years, 9 months ago (Nov. 21, 2003)
Published Print	21 years, 9 months ago (Nov. 21, 2003)

Funders 0

None

BibTeX

@article{Svenningsson_2003, title={Diverse Psychotomimetics Act Through a Common Signaling Pathway}, volume={302}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1089681}, DOI={10.1126/science.1089681}, number={5649}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Svenningsson, Per and Tzavara, Eleni T. and Carruthers, Robert and Rachleff, Ilan and Wattler, Sigrid and Nehls, Michael and McKinzie, David L. and Fienberg, Allen A. and Nomikos, George G. and Greengard, Paul}, year={2003}, month=nov, pages={1412–1415} }

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